Two independent reviews, both published ahead-of-print in the Annals of Internal Medicine, that assessed data from all of Medtronic’s trials of recombinant human bone morphogenetic protein 2 (rhBMP-2), have reported that the product has little or no clinical benefit compared with bone graft—with one review concluding that it is difficult to identify clear indications for the use of rhBMP-2 in spinal fusion.
Two years ago, after The Spine Journal dedicated an issue to a heavily critical review of the data for rhBMP-2, the product’s manufacturer Medtronic took the unprecedented step of providing the Yale University Open Data Access (YODA) project with all of its patient-level data for rhBMP-2—including that from unpublished studies as well as published studies. Two teams of researchers, as part of the YODA project, then conducted two separate reviews of these data and other data concerning rhBMP-2. Neither team had access to the other team’s findings until after both reviews were accepted for publication in the Annals of Internal Medicine.
In their review, Rongwei Fu (Oregon Health & Science University, Portland, USA) and others assessed data from 17 industry-sponsored studies, related internal documents, and searches of MEDLINE and other databases. They found that in patients undergoing anterior lumbar interbody fusion, there was “moderate-strength evidence” that there were no consistent differences between rhBMP-2 and iliac crest bone graft in “overall success, fusion rates, or other effective measures from six weeks through 24 months after surgery”. Fu et al added that they were also not able to find evidence of consistent differences in clinical benefit between rhBMP-2 and bone graft in patients undergoing posterior lumbar fusion or cervical fusion.
The authors also reported that with anterior lumbar interbody fusion and posterior lumbar fusion, they did not identify any significant differences in the rate of adverse events between rhBMP-2 and bone graft. However, in the context of anterior cervical spine fusion, rhBMP-2 was associated an increased risk of wound complications and dysphagia.
Furthermore, they commented: “Compared with the control groups, rhBMP-2 was associated with an increased risk for cancer; absolute difference, 1.9 percentage points with a number needed to harm of 53. Data were insufficient to determine the effect of rhBMP-2 on estimates of cancer risk.”
Also, according to Fu et al, there was “substantial evidence” of reporting bias in the studies of rhBMP-2. One of The Spine Journal’s main criticisms of the original rhBMP-2 studies was the under reporting of adverse events and that the investigators did not fully declare their conflicts of interests regarding their relationship with Medtronic. Last year, a US Senate Finance Committee report accused Medtronic of publishing studies that may have “inaccurately represented” the risk of rhBMP-2.
Concluding their findings, Fu et al said: “On the basis of the currently available evidence, it is difficult to identify clear indications for rhBMP-2 in spinal fusion.”
The results of the second review (which used patient-level data from 11 of 17 Medtronic-sponsored studies), by Mark Simmonds (Centre for Reviews and Dissemination, University of York, York, UK) and others, were similar to the result of Fu et al’s review. They found that after 24 months, that rhBMP-2 was associated with a significantly increased rate of fusion compared with iliac crest bone graft. However, they did not find that this increased rate of fusion translated into a clinical significant reduction in pain. Simmonds et al reported that while, from six months onwards, the use of rhBMP-2 was associated with greater reduction in pain than was the use of bone graft, patients in both groups improved considerably over time “such that the extra benefit of rhBMP-2 over iliac bone graft surgery was small in comparison”. Additionally, the authors stated that they found “clear evidence” of greater pain at or shortly after surgery in patients treated with rhBMP-2.
As with Fu et al’s review, Simmonds et al’s review found evidence of association between rhBMP-2 and an increased risk of cancer. They wrote: “A one-stage randomised-effects meta-analysis model found that cancer was nearly twice as common among rhBMP-2 recipients” but added that the absolute risk for cancer was lower (3%) and commented: “Whether this increased risk is genuine is uncertain, but it is consistent with the literature suggesting a possible link between bone morphogenetic protein and cancer.”
In their conclusion, Simmonds et al wrote: “We believe it is important that clinicians explain these findings to patients so that they can make informed choices about the type of surgery they would prefer.”
Lesley Stewart, who led the research for the second review, spoke to Spinal News International about the importance of having all of the data available. She said: “To reach a fair and unbiased judgement about any intervention, it is important to be able to examine all of the relevant data, irrespective of whether or not it is published. Having access to all the data from each of the individual patients included in the studies enabled us to do much more detailed analysis than had we been restricted to using an incomplete summary of data from reports. Systematic reviews that use individual participant data are internationally accepted as the gold standard.”
Implications for rhBMP-2
In accompanying editorial, Annals of Internal Medicine editor-in-chief Christine Laine wrote: “The fact that two independent groups armed with the same question and the same patient-level data, along with guidance of two independent sets of reviewers and editors, arrived at essentially the same conclusions should greatly temper enthusiasm for the intervention.”
In another accompanying editorial, spinal surgeons Daniel Resnick (University of Wisconsin, Wisconsin, USA) and Kevin J Bozic (University of California, San Francisco, USA) wrote that the YODA studies provided a valuable insight into the potential benefits and harms of rhBMP-2. They added: “Given the higher complication rates noted in anterior cervical surgery, rhBMP-2 should not be used in this setting without a compelling reason—for example, during a pseudoarthrosis repair or other salvage procedure.” However, Resnick et al commented that the reviews showed that it seemed “clinically reasonable” to used autotgraft or rhBMP-2 to enhance fusion rates in patients having anterior lumbar interbody fusion or posterolateral fusion. They added: “In some procedures, such as anterior lumbar interbody fusion, graft harvest is a separate procedure and avoiding a second incision and associated graft site pain may well be worth the exceedingly small risk for cancer.”
Chris O’Connell, executive vice president and president of Medtronic’s Restorative Therapies Group, including the Spine business, said: “We are pleased to have reached a milestone in completing this review as we move forward with this important treatment option. We remain committed to Infuse bone graft, which has a decade of clinical use and has been cited as one of the most important innovations in orthopaedic medicine.”